The HIV-proteinase is essential for the proteolytic processing of the viral gag and gag-pol precursor proteins. This has been shown to be structurally and functionally related to aspartyl proteinases. We have studied the inhibition of HIV-replication in lymphocyte cell culture by Cerulenin, a naturally occurring antifungal antibiotic, as well as by Zn2+. We report here for the first time that the combination of Cerulenin and Zn2+ in proper modality, inhibits HIV-replication in C-8166-45 transformed human umbilical cord blood lymphocytes 90%, which is comparable to the potency of inhibition by AZT. We have studied the inhibition of HIV replication by Cerulenin and Zn2+ individually also, in the culture which has very limited activity and toxic too at higher dosages.